Nanomedicine-based anti-neuroinflammation strategy has become a promising dawn of Parkinson’s disease (PD) treatment. However, there are significant gaps in our understanding of the therapeutic mechanisms of antioxidant nanomedicines concerning the pathways traversing the blood-brain barrier (BBB) and subsequent inflammation mitigation. Here, we report nanozyme-integrated metal-organic frameworks with excellent antioxidant activity and chiral-dependent BBB transendocytosis as anti-neuroinflammatory agents for the treatment of PD. These chiral nanozymes are synthesized by embedding ultra-small platinum nanozymes (Ptzymes) into L-chiral and D-chiral imidazolate zeolite frameworks (Ptzyme@L-ZIF and Ptzyme@D-ZIF). Compared to Ptzyme@L-ZIF, Ptzyme@D-ZIF shows higher accumulation in the brains of male PD mouse models due to longer plasma residence time and more pathways to traverse BBB, including clathrin-mediated and caveolae-mediated endocytosis. These factors contribute to the superior therapeutic efficacy of Ptzyme@D-ZIF in reducing behavioral disorders and pathological changes. Bioinformatics and biochemical analyses suggest that Ptzyme@D-ZIF inhibits neuroinflammation-induced apoptosis and ferroptosis in damaged neurons. The research uncovers the biodistribution, metabolic variances, and therapeutic outcomes of nanozymes-integrated chiral ZIF platforms, providing possibilities for devising anti-PD drugs.

Treatment for Parkinson’s disease (PD) has been impeded by inefficient treatment results and multiple membrane barriers during drug delivery. This study reports the design, synthesis, and application of microneedles (MNs) loaded with mitochondrion-targeted liposome encapsulated iron (Fe)-isolated single-atom nanozymes (Mito@Fe-ISAzyme, MFeI), called MFeI MNs, for in situ drug delivery into the brain parenchyma and efficient enrichment of drugs in lesion sites. In in vitro experiments, MFeI can scavenge reactive oxygen species (ROS) and protect the neurons via mitochondrial targeting, guaranteeing the subsequent treatment of PD. Using PD mouse models, we compared the intravenous injection of MFeI with the brain in situ administration of MFeI MNs (in situ MFeI MNs). Results showed that in situ MFeI MNs significantly improved the deep penetration of the drug into brain parenchyma, especially in the vital pathological sites such as the substantia nigra pars compacta and striatum. Importantly, ROS elimination and neuroinflammatory remission in the lesion site were observed, thereby efficiently alleviating the behavioral disorders and pathological symptoms of PD mice. Therefore, the MNs system for in situ single-atom nanozyme liposome delivery exhibits great potential in PD treatment.

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder accompanied by movement disorders and neuroinflammatory injury. Anti-inflammatory intervention to regulate oxidative stress in the brain is beneficial for managing PD. However, traditional natural antioxidants have failed to meet the clinical treatment demands due to insufficient activity and sustainability. Herein, Cu-doping zeolite imidazolate framework-8 (ZIF-8) nanozyme is designed to simulate Cu/Zn superoxide dismutase (SOD) by biomimetic mineralization. The nanozyme composite is then integrated into thermosensitive hydrogel (poly (lactic-co-glycolic acid)-poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PLGA-PEG-PLGA)) to form an effective antioxidant system (Cu-ZIF@Hydrogel). The thermosensitive hydrogel incorporating nanozymes demonstrate distinct viscoelastic properties aimed at enhancing local nanozyme adhesion, prolonging nanozyme retention time, and modulating antioxidant activity, thus significantly improving the bioavailability of nanozymes. At the cellular and animal levels of PD, we find that Cu-ZIF@Hydrogel bypass the blood-brain barrier and efficiently accumulate in the nerve cells. Moreover, the Cu-ZIF@Hydrogel significantly alleviate the PD’s behavioral and pathological symptoms by reducing the neuroinflammatory levels in the lesion site. Therefore, the hydrogel-incorporating nanozyme system holds great potential as a simple and reliable avenue for managing PD.

The complex pathology of Parkinson's disease (PD) requires comprehensive understanding and multi‐pronged interventions for communication between nerve cells. Despite new developments in nanotechnology in the treatment of PD, in‐depth exploration of their biological effects, in particular, the specific mechanisms of inflammation inhibition are lacking. Herein, using the stable cascade catalysis channel formed by polydopamine (PDA), imidazole groups, and Cu ions, a microgel system comprising functional monomers [superoxide dismutase (SOD) with double bonds, PDA, 2‐methacryloyloxy ethyl phosphorylcholine (MPC), and Cu ions] is proposed for managing PD. The microgel can be efficiently delivered to the brain aided by MPC, after which a multi‐level regulatory strategy targeting neurons and microglia can be initiated. The catalytic activity cascade elicited by SOD and Cu ions can regulate the anti‐inflammatory phenotypic transformation of microglia by relieving oxidative stress. Meanwhile, the dopamine (DA) released from PDA can facilitate DA storage and neurogenesis, inhibiting CX3CL1 release and the CX3CR1 receptor on microglia and further regulating the CX3CL1/CX3CR1‐NF‐κB‐NLRP3 signaling pathway in microglia to inhibit neuroinflammation. Therefore, the proposed microgel delivery system with functional monomers represents a promising therapeutic strategy for managing neuroinflammation and promoting neurogenesis in PD by intervening chemokine axis‐mediated communication between neurons and microglia.

Lack of adequate effector T cells infiltrated in tumor is one of the main problems in the failure of immune checkpoint blockade therapy (ICBT). Photodynamic therapy (PDT) induced acute inflammation can sensitize tumors and activate T cells, thus assisting immune checkpoint inhibitors (ICI) against tumor growth and metastasis. T cells maturation and activation lag 3 to 7 days behind PDT. However, such timing in the combination therapy of ICI and PDT is commonly ignored in designing numerous multi‐functional integrated nanomedicines. Herein, the authors illustrate that intervention timing of ICI after PDT affects the anti‐tumor efficacy. A tumor‐targeting nanomedicine is prepared by encapsulating indocyanine green into CD44 specifically binding material, a hyaluronic acid conjugated lipid poly(ethylene glycol). The PDT nanomedicine is designed to induce a robust immune response in tumor. The optimal group (Combo‐STAR), ICI gave 5 days after PDT, significantly suppresses local tumor growth and eliminates metastasis. What should be highlighted is the time point of administration because if ICI is given too early, T cells are immature, otherwise, T cells are exhausted if ICI is given too late. This work presents theoretical guidance for raising awareness of intervention timing when augmenting ICBT with immune response inducers in clinic.